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RNA-Seq of PARPi-resistant ovarian cancer cells

ABSTRACT: We have previously established an in vitro model of PARPi-resistant ovarian cancer by long-term exposure of UWB1.289 ovarian cancer cells (and their isogenic derivatives UWB1.289+BRCA1) to incrementally ascending olaparib concentrations. After finalizing this model, we performed RNA-seq, in order to identify differentially expressed transcript in the PARPi-resistant cells, with a focus on genes related to DNA-repair, multi-drug resistance and EMT. As a result, we show that the phenotype of PARPi resistance is associated with EMT-like traits and up-regulation of selective multi-drug related transcripts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235980 | GEO | 2023/07/31

REPOSITORIES: GEO

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Project description:Extending the therapeutic spectrum of PARP-inhibition (PARPi) beyond HR-deficiency or reverting PARPi resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a promising strategy for defining new therapeutic standards. In this study, we analysed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with PARPi. This is the first study analysing the potential therapeutic effect of these components. In vitro assays for drug characterization including RNA-seq were applied in a selected panel of ovarian cancer cell lines. CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the micro- to almost millimolar range (107-940µM), whereas its metabolite CT913-M1 was about 10-fold more potent (IC50 of 17-93µM). Neither of the drugs increased the cytotoxic effect of cisplatin, CT913 might even antagonize it. Furthermore, CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that homologues recombination (HR) repair may contribute to its mechanism of action. Importantly, CT913 sensitized for olaparib treatment, independently of BRCA-1 mutational status, supporting the finding that CT913 may act partially independent of an impaired HR. CT913 treatment led to changes in gene transcription. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It also downregulated a variety of transcripts involved in prominent DNA-repair pathways, such as HR, mismatch repair (MMR) or nucleotide excision repair (NER). This is the first study, suggesting the triazene drug class CT913 as auxiliary drug for extending the therapeutic spectrum of PARPi.

Project description:Epithelial ovarian cancer (EOC) is the most serious of all gynecological cancers, mainly due to its asymptomatic nature and the resulting lack of early diagnosis. Cells with defects in DNA repair accumulate genetic abnormalities and may progress to become malignant. However, this DNA repair deficiency makes tumor cells vulnerable to further compromise by therapeutic targeting of other associated pathways, using agents such as poly-ADP ribose polymerase (PARP) inhibitors (PARPIs). A major challenge facing the use of PARPIs is the paucity of functional assays/biomarkers to identify HGSOC patients who may benefit from these agents, in particular the subgroup with non-BRCA-mutant, HR-deficient cancers. Our study presents a predictive tool which may help identify sporadic HGSOC patients, most likely to respond to PARPIs therapy. We have successfully developed and employed a functional 3D assay to test PARPIs sensitivity in EOC based on ascites-derived primary cell cultures (AsPCs) from EOC patients. Our data showed that this approach can better mimic primary tumor response to PARPIs treatments. We have successfully grown 42 AsPCs, and have prepared spheroid cultures from AsPCs using 3D-Biomatrix technology. We were able to monitor the cytotoxic effect on AsPCs spheroids of each of the drugs olaparib (Astra- Zeneca) and niraparib (Tesaro, licensed from Merck). Our results showed that AsPCs appear to be much more sensitive to niraparib compared to olaparaib. The cytotoxic effect observed by the two drugs was confirmed by analysis of γH2AX foci formation. Data demonstrated γH2AX foci to significantly increase in cell lines that are sensitive to the drug treatments. Consecutively, epithelial-to-mesenchymal transition (EMT) was also assessed in resistant vs. sensitive cell lines. Our results indicate that PARP inhibition can inhibit the acquisition of an EMT phenotype in sensitive cell lines, but not in resistant cell lines. Moreover, global gene and microRNA expression profiling of PARPI-R and PARPI-S spheroid cultures identifies gene/mRNA biomarkers, associated with PARPI sensitivity. We believe our predictive tool has helped classify genes that can be clinically relevant in identifying PARP inhibitor sensitivity in ovarian cancer.

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RNA-Seq of PARPi-resistant ovarian cancer cells

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